Somatic mutations in melanoma | ПРЕЦИЗИОННАЯ ОНКОЛОГИЯ

Somatic mutations in melanoma

BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)

UV damage-induced mutations

Somatic driver mutations identified in patient tumors, both in melanoma and other cancers, tend to be recurrent single nucleotide changes in oncogenes, with mutations leading to stop codons and frameshift mutations, and insertion and deletions as observed in tumor suppressor genes. Likewise, critical genomic aberrations also exist and include loss of heterozygosity or amplification at specific loci, splice variants, and epigenetic dysregulation. As such, the molecular diagnostic testing of melanoma tumor samples needs to reliably detect these diverse somatic mutations and genomic aberrations, since identification of these mutations in patient tumors is critical for the determination of appropriate therapy.

Notably, samples from melanoma cell lines and tumor samples have demonstrated mutations consistent with UV exposure [22], which is a known risk factor for the development of melanoma [23–25]. Pyrimidine dimers are characteristic of UVinduced DNA damage and mutations are predominantly C to T/G to A transitions, along with CC to TT transitions [26, 27]. These mutations are frequently observed in adjacent pyrimidine sequences and at higher frequencies of CpG dinucleotides. Indeed, massively parallel sequencing of a melanoma cell line derived from a metastatic tumor sample demonstrated increased C to T transitions in bases at pyrimidine dinucleotides (92%, as compared to predicted 53% due to chance) and at CpG dinucleotides (10%, as compared to predicted 4.4% due to chance) [22]. Whole exome sequencing of larger numbers of melanoma tumor samples, 121 melanoma tumor/normal pairs and 147 melanoma tumor samples, confirmed these observations of UV-induced damage [20, 21] along with identification of different mutation patterns in tumors from sun-exposed and sun-shielded sites [21]. Cells have a number of mechanisms for repairing DNA damage. In UV-induced DNA damage, nucleotide excision repair (NER) is the predominant mechanism for DNA damage repair [22, 28, 29], with preferential repair of actively transcribed strands [22, 27, 30, 31]. Results from massively parallel sequencing of melanoma tumor samples demonstrate that fewer somatic mutations are identified on transcribed DNA strands within genes than non-transcribed strands, consistent with transcription coupled repair [21, 22]. UV-induced DNA damage is highly prevalent in melanoma tumor samples from sun-exposed areas. However, somatic mutations due to UV-induced DNA damage are under-represented as causative driver mutations in melanoma, as cells have developed mechanisms to repair DNA damage through NER. The converse is observed in tumors derived from xeroderma pigmentosum (XP), a hereditary syndrome characterized by deficient nucleotide excision repair. In these tumor samples, patterns of somatic mutations in key tumor suppressor genes, including TP53, are a result of deficient NER, with significant UV-induced DNA damage, although preferential transcription-coupled repair is preserved [26, 27].

BRAF mutations

BRAF is the most common driver mutation identified in melanoma tumor samples and is mutated in approximately 50% of melanomas [32–34]. Within BRAF, the most prevalent mutation is a glutamic acid substitution for valine at codon 600 (?BRAF V600E) which occurs in the kinase domain and results in a constitutively active protein [32–34]. Additional BRAF V600 and proximate mutations are observed in melanoma cell lines and tumor samples, as well as in the loop domain (exon 11) [34–36]. The BRAF V600E mutation is associated with younger age of diagnosis and truncal site of primary lesion [36, 37]. The BRAF V600K mutation is a result of a two base change within codon 600; it has been observed in 9–19% of melanomas and is associated with increased age and higher cumulative sun damage [37, 38]. Improved clinical response to targeted BRAF inhibition compared to chemotherapy has been observed in patients whose melanomas carry BRAF V600E and V600K mutations [3, 11, 12, 36]. However, lower response rates to targeted BRAF inhibition are observed in patients with BRAF V600K mutant melanoma [39, 40]. The BRAF V600 inhibitors were developed to target the mutated protein. Thus, it is not entirely clear whether patients with melanomas harboring the non-V600 BRAF mutations will respond similarly to BRAF inhibition. Dahlman et al. [41] demonstrate both preclinical and clinical data supporting the use of targeted inhibition of the MAPK pathway in BRAF L597 mutated melanoma. A patient with BRAF L597S mutated metastatic melanoma responded to treatment with the MEK inhibitor, TAK-733 [41]. In addition, preclinical data suggest that BRAF K601 mutant melanomas may respond to treatment with MEK inhibitors; as expression of BRAF K601E induced signaling through the MAPK pathway was abrogated with MEK inhibition [41]. Further studies are needed to determine the role of BRAF and/or MEK inhibition in non-BRAF V600 mutant melanoma.

NRAS mutations

NRAS mutations are the second most prevalent mutations, and are found in 15–20% of melanomas [42–44]. The predominant mutations in NRAS occur in exon 2 at codon 61 with substitution of glutamine with several different amino acids (Q61) [45, 46], resulting in activation leading to uncontrolled cell proliferation. In addition, somatic mutations have been identified in exon 1 at codons G12 and G13 [47]. NRAS Q61 mutations are associated with the nodular subtype of melanoma, increased tumor thickness, and worsened clinical outcome, demonstrating shorter melanoma specific survival time [38, 42, 48, 49]. It has been challenging to target RAS mutations in tumors generally, however, current clinical trials are underway investigating the use of MEK inhibitors (?MAP2K1 and MAP2K2, mitogen-activated protein kinase 1 and 2) either as single agents or in combination with parallel intracellular signaling pathway inhibitors, such as PI3K/mammalian target of rapamycin (mTOR) inhibitors to treat NRAS-mutant melanomas [50–53] (

KIT mutations

KIT is a receptor tyrosine kinase and is mutated in a small percentage of cutaneous melanomas. However, mucosal and acral lentiginous melanomas, along with melanomas arising in chronic sun-damaged skin, have an increased prevalence of KIT mutations; mutations and increased copy number have been identified in approximately 30% of these specific melanoma subtypes [54, 55]. Somatic mutations in KIT have been observed in a number of different exons including 9, 11, 13, and 17. As there is no single predominant mutation in KIT, molecular testing must evaluate multiple exons within the gene. Variable responses to treatment with imatinib, a KIT and PDGFR tyrosine kinase inhibitor, have been observed in patients with melanomas with KIT mutations [13–18]. Several studies have found that the maximal response to imatinib is seen in patients whose melanomas have KIT mutations in exons 11 and 13 [13, 14]. Responses have also been observed upon treatment with dasatinib, a tyrosine kinase inhibitor similar to imatinib, in melanoma [19].

Approximately 30% of melanoma tumors do not contain mutations in BRAF, NRAS, or KIT genes, and therefore do not currently have mutations that can be therapeutically targeted. However, additional driver mutations in melanomas have been identified, which may lead to the eventual development of appropriate targeted therapies. In particular, massively parallel sequencing has delineated mutations in ARID2, NF1, PPP6C, RAC1, SNX31, STK19, and TACC1 [20, 21]. PPP6C is a component of the PP6 protein phosphatase complex and a proposed tumor suppressor; it functions to regulate cyclin D1 during cell cycle progression [56, 57]. STK19 is thought to encode a kinase of unknown function and mutations within this gene are identified within hotspot regions in melanoma tumor samples [20]. RAC1 is a member of the Rho family of GTPases and functions in melanocyte proliferation and cell migration through its role in cell adhesion, migration, and invasion [20, 21, 58]. With the data from several published studies using whole exome and genome massively parallel sequencing in melanoma [20–22,59–62], as well as the on-going Cancer Genome Atlas effort, the spectrum of genetic mutations and genomic aberrations in untreated cutaneous melanoma is likely to be well described in the near future. With the routine use of targeted therapies in the treatment of BRAF mutated melanoma, clinicians have observed resistance to therapy. Discovery of additional or acquired mutations in these tumor samples is important for identification of resistance mechanisms, which may fall outside the spectrum of mutations observed in untreated melanomas, with the eventual goal of preventing and overcoming these mechanisms of resistance.

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